C. G. Schmidt

Untersuchungen zur kurzzeitigen Induktions- und zyklischen Erhaltungstherapie beim inoperablen kleinzelligen Bronchialkarzinom

Since July 1978 one hundred and three consecutive patients with unresectable small cell bronchogenic carcinoma were treated with a combination of doxorubicin, cyclophosphamide and vincristine (ACO). In limited disease patients (64) the second chemotherapy course was followed by prophylactic cranial irradiation, the fourth by irradiation towards primary disease sites. Complete responders were randomised to either receive etoposide or no further maintenance therapy. Objective responses were reached in 88/100 evaluable patients, with 72% of complete remissions in limited-stage disease and 33% in extensive disease, respectively. The actuarial median survival time for limited disease patients was 15.8 months compared to 9.3 months in extensive disease (p less than 0.005). 29 of the 100 patients remain still alive, 4 for more than 24 months without disease recurrence. The survival advantage of patients reaching complete remissions relative to those who did not is highly significant (p less than 0.001). Acute gastrointestinal and hematological side effects were common, with possibly three drug-related deaths from infections during transient granulocytopenia (mean nadir: 600-900 cells/mm3). The present induction regimen using only four courses of chemotherapy produces high complete remission rates on roentgenography and bronchoscopy and improved survival in the majority of patients. Thus far any effectiveness of etoposide-maintenance therapy following ACO could not be substantiated.SummarySince July 1978 one hundred and three consecutive patients with unresectable small cell bronchogenic carcinoma were treated with a combination of doxorubicin, cyclophosphamide and vincristine (ACO). In limited disease patients (64) the second chemotherapy course was followed by prophylactic cranial irradiation, the fourth by irradiation towards primary disease sites. Complete responders were randomised to either receive etoposide or no further maintenance therapy. Objective responses were reached in 88/100 evaluable patients, with 72% of complete remissions in limited-stage disease and 33% in extensive disease, respectively. The actuarial median survival time for limited disease patients was 15.8 months compared to 9.3 months in extensive disease (p<0.005). 29 of the 100 patients remain still alive, 4 for more than 24 months without disease recurrence. The survival advantage of patients reaching complete remissions relative to those who did not is highly significant (p<0.001). Acute gastrointestinal and hematological side effects were common, with possibly three drug-related deaths from infections during transient granulocytopenia (mean nadir: 600–900 cells/mm3). The present induction regimen using only four courses of chemotherapy produces high complete remission rates on roentgenography and bronchoscopy and improved survival in the majority of patients. Thus far any effectiveness of etoposide-maintenance therapy following ACO could not be substantiated.ZusammenfassungSeit Juli 1978 wurden 103 Patienten mit inoperablem kleinzelligem Bronchialkarzinom mit der Zytostatikakombination Adriamycin, Cyclophosphamid und Vincristin (ACO) behandelt. Im Stadium „limited disease“ (n=64) erfolgte während des zweiten Chemotherapiekurses eine prophylaktische Schädelbestrahlung, nach dem vierten eine konsolidierende thorakale Bestrahlung. Nach Erreichen einer kompletten Remission erhielten die Patienten prospektiv randomisiert Etoposid oder keine weitere spezifische Therapie. Ein objektives Ansprechen konnte bei 88/100 auswertbaren Patienten erzielt werden. Im Stadium „limited disease“ fanden sich 72%, im Stadium „extensive disease“ nur 33% komplette Remissionen. Im Stadium „limited disease“ betrug die hochgerechnete mediane Überlebenszeit 15,8, im Stadium „extensive disease“ 9,3 Monate (p<0.005). Es leben noch 29 Patienten, 4 rezidivfrei länger als 24 Monate. Patienten mit kompletter Remission hatten eine statistisch signifikant (p<0.001) längere Überlebenszeit als Patienten mit geringerem Ansprechen. Regelmäßig traten gastrointestinale und hämatologische Nebenwirkungen auf, drei Patienten starben während der Induktionsphase an Infektionen. Die kurzzeitige Induktionsbehandlung verbesserte jedoch den Krankheitsverlauf subjektiv und objektiv. Bisher ist kein positiver Effekt der zyklischen Etoposid-Gabe nach ACO festzustellen.

Crossover comparison of the antiemetic efficacy of nabilone and alizapride in patients with nonseminomatous testicular cancer receiving cisplatin therapy

SummaryTwenty nonseminomatous testicular cancer patients not pretreated with emetogenic chemotherapy were included in a crossover study of antiemetic therapy. Patients were randomly assigned to receive either nabilone (2×2 mg/day) or alizapride (3×150 mg/day) prior to beginning lowdose cisplatin chemotherapy. Patients on nabilone had significantly fewer episodes of emesis than those on alizapride (medians, 1.1 vs 2.9;p<0.01). Nabilone was superior to alizapride in giving complete relief from nausea (medians, 65% vs 30%;p<0.01), and was more effective in shortening the duration of nausea (medians, 1.3 h vs 5.1 h;p<0.01); however, it caused more adverse effects. It is concluded that nabilone has greater antiemetic activity than alizapride in young patients receiving low-dose cisplatin chemotherapy. Nabilone dosage should be reduced to decrease the incidence and degree of adverse reactions while leaving the definite antiemetic activity unchanged.

Pronounced Antiemetic Activity of the Antipsychotic Drug Levomepromacine (L) in Patients Receiving Cancer Chemotherapy

ZusammenfassungUnter stationär-klinischen Bedingungen wurde die zufällig beobactete antiemetische Qualität des oral angewandten Phenothiazinderivats Levomepromazin bei Tumorpatienten untersucht, welche entweder mit Cisplatin, Iphosphamid oder Adriamycin-haltigen Kombinationen behandelt wurden.Alle auswertbaren Patienten waren refraktät genenüber konventionellen Antiemetika. Bei einer Gesamtzahl von 113 Patienten konnte in insgesamt 70 Fällen (62%) ein voller Schutz vor Übelkeit und Erbrechen durch eine zweimalige Anwendung von Levomepromazin in einer Dosierung von 8–15 mg je 12 Std und 1 Std vor Beginn der Chemotherapie bewirkt werden. Bei weiteren 34% aller Patienten war eine deutliche subjektive Besserung hinsichtlich der gastrointestinalen Nebenwirkungen zu verzeichnen. Am ausgeprägtesten war der antiemetische Effekt von Levomepromazin bei Patienten unter konventioneller Cisplatin-Therapie (20 mg/m2 täglich×5), jedoch konnte eine eindeutige Wirkung auch bei hohen Cisplatindosen bis 100 mg/m2, welche normalerweise zusehr starken Nebenerscheinungen führten, nachgewiesen werden. Darüber hinaus war der antiemetische Effekt von Levomepromazin auch gegen Übelkeit und Erbrechen im Zusammenhang mit Adriamycin oder Iphosphamid wirkungsvoll. Obwohl eine endgültige Beurteilung des antiemetischen Effekts von Levomepromazin erst auf der Basis einer Doppelblindstudie möglich sein wird, was das Medikament bereits bei zahlreichen Patienten von großem Wert für die praktische Durchführung einer effektiven Zytostatikathepie.SummaryThe antiemetic quality of the orally administered phenothiazine derivative levomepromacine was studied under clinical conditions in cancer patients receiving either cisplatin alone, ifosfamide alone or adriamycincontaining combinations.Seventy of 113 evaluable patients (62%)-all refractory to conventional antiemetics-were fully protected from nausea and vomiting when levomepromacine (2×8–15 mg) was administered in two steps (12 h and 1 h before the cytotoxic agents). Another 34% of all patients showed considerable improvement with respect to gastrointestinal side effects. The most pronounced effect with levomepromacine was seen in patients treated with a 20 mg/m2 daily×5 schedule of cisplatin but complete or partial relief was also seen with high single cisplatin doses of 50–100 mg/m2. In addition, the antiemetic showed effectiveness against nausea and vomiting induced by other agents, such as adriamycin or isofosfamide. Although a final evaluation of the antiemetic effect of levomepromacine will have to be based on a double-blind study, these initial observations have already been of great value for many patients.

Phase II evaluation of fractionated low and single high dose cisplatin in various tumors

SummarySeventy-three evaluable patients with advanced measurable solid tumors were given cisdichlorodiammineplatinum (II) (DDP) at a dose of 20 mg/M2 IV for 1–5 days every 3 weeks, and 19 patients who failed on this low dose DDP protocol received a single high dose of 100 mg/M2 IV once every 3 weeks. Forty-six patients had received prior chemotherapy, and 29 patients were untreated. Results included four complete responses (5.5%) in malignant melanoma, spindle-cell sarcoma, adrenal carcinoma, and bladder carcinoma lasting 2 to 4 months. In 21 patients (28.8%), partial responses were achieved. Twenty-two patients (30.1%) showed stable disease and 26 (35.6%) had tumor progression. A response rate of 25% (4/16 patients) was found for malignant melanoma, 45.5% (5/11) for nonsmall-cell lung cancer, and 35.3% (6/17) for sarcomas of various types. One patient with teratocarcinoma, who relapsed on low-dose DDP, had another partial remission for 4 months after high-dose therapy. Toxicity was most commonly seen with gastrointestinal side effects and myelosuppression. Cumulative nephrotoxicity was prevented by prehydration and/or treatment with furosemide or mannitol.

Autonomous cortisol secretion by a metastatic Leydig cell carcinoma associated with Klinefelter's syndrome

SummaryWe present the case of a 39-year-old man with Klinefelters syndrome and metastatic Leydig cell carcinoma in whom autonomous cortisol production induced by the interstitial cell tumor was found. Apart from the Cushings syndrome the endocrine activity of the tumor was demonstrated by the secretion of estradiol, estrone, alkaline phosphatase, and testosterone. This is, to our knowledge, the first description of a Cushings syndrome not caused via ACTH production but directly induced by ectopic steroid production. While being resistent to chemotherapy and radiation, the tumor responded favorably to treatment with o,p′-DDD. The reduction of tumor size was accompanied by a continuous decrease of serum markers.The etiology of the tumor is discussed in the light of the hormonal derangement caused by the genetic abnormality of Klinefelters syndrome.ZusammenfassungWir berichten über einen 39jährigen Patienten mit einem Klinefelter-Syndrom, bei dem sich die autonome Produktion von Cortisol durch einen metastasierenden Leydig-Zell-Tumor nachweisen ließ. Die endokrine Tumoraktivität zeigte sich — neben einem Cushing-Syndrom — in der abnormen Sekretion von Östradiol, Östron, alkalischer Phosphatase und Testosteron. Es handelt sich dabei unseres Wissens um den ersten beschriebenen Fall eines Cushing-Syndroms, das nicht über die Bildung von ACTH, sondern durch ektope Steroidproduktion verursacht wurde.Bei fehlender Radio- und Chemotherapiesensibilität zeigte sich eine Tumorrückbildung während der Behandlung mit o,p′-DDD, die mit einem dauerhaften Abfall der biologischen Tumormarker verbunden ist. Die Ätiologie des Tumors im Zusammenhang mit dem Klinefelter-Syndrom wird besprochen.

Efficacy of gamma and alpha interferon (IFN) in the treatment of hairy cell leukemia (HCL)

Hairy-cel l leukemia is a B-cel l tumor in which IFN-~has recent ly been shown to have a clear antitumor ef fect . In order to elucidate the action of IFN in HCL we studied the the ef fect of human recombinant IFN-alpha-2 on pur i f ied peripheral blood hairy ce l ls and a hairy ce l l leukemia line(HCL-1). Since IFN can promote cel l d i f f e ren t i a t i on of various tumor cel l l ines , morphological and immunophenotypic d i f f e ren t i a t i ng effects were studied in de ta i l . In the presence of IFN-~ the leukemic hairy ce l ls los t most of the i r typ ica l v i l l ous membrane project ions and became nonadherent to glass and p las t i c surfaces. Surface marker analysis was carr ied out using the monoclonal antibodies FMC-7, OKlal, Leu-M3, ant i-Tac, T015, BMA 030, and Lyt3, React iv i ty with the monoclonals Lyt3 and BMA 030 was found to be induced by IFN. In contrast, IL-2 receptor expression was down-regulated by IFN treatment. From these results we conclude that IFN-alpha-2 exerts a profound d i f feren t i a t i ng action on hairy ce l ls in v i t r o .

4′-Epi-doxorubicin — A clinical phase-II trial in solid tumors

Summary4′-Epi-doxorubicin is a new anthracycline analog with reduced cardiac toxicity in animal studies. A phase-II study was performed in 17 patients predominantly with non-small-cell lung cancer. All suffered from recurrent or advanced tumors and 7 of 16 evaluable patients had been pretreated with an alternative chemotherapy. 4′-Epi-doxorubicin was applied at a dose of 75 mg/m2 every 3–4 weeks. The median total dose was 280 mg (range: 130–250 mg). Only one patient with epidermoid lung cancer (overall response rate: 6%) showed a minor response and stable disease was observed in six other patients with bronchogenic carcinoma. Myelosuppression was rare and moderate: Leukocytopenia of less than 2,000/mm3 occurred in 25% of patients and thrombocytopenia of less than 100,000/mm3 in 8% of patients. The frequency of alopecia and gastrointestinal side effects was 88% and 80%, respectively. Persistent electrocardiographic alterations were recorded in 2 of 14 (14%) patients. One of four patients revealed a marked reduction of left ventricular ejection fraction in radionuclide cardiography. It is concluded that 4′-epi-doxorubicin is not superior to adriamycin in this low-prospect treatment area, but studies with increased doses appear necessary in adriamycin-sensitive tumors because of recent reports from phase-III trials showing reduced cardiac and gastrointestinal toxicity with 4′-epi-doxorubicin in comparison with adriamycin.

Predictive tests in cancer chemotherapy a reappraisal

SummaryThe evolution of medical oncology so far owes much to the preclinical and clinical development of antineoplastic agents. Prognostic factors and empiric treatment strategies have guided the clinician in his choice of drugs. In the light of increasing ethical restrictions met with phase I–II clinical trials and major advances in propagating human tumor cells outside the donor patient, a reappraisal of predictive tests in cancer chemotherapy is warranted. Among ‘short-term assays’ only the determination of steroid-hormone receptor content in tumor tissues has gained clinical acceptance, whereas other methods still suffer from theoretical or practical shortcomings.Both the human tumor stem cell assay and the xenograft model have revealed unique patterns of sensitivity for each individual tumor line. While interindividual heterogeneity among tumors sharing a common site of origin justifies efforts to develop predictive tests, microheterogeneity among tumor samples from the same donor patient limits the potential of this approach.Predictive tests should be performed in conjunction with clinical trials to ensure optimal extraction of information. As additional prognostic factors, they should in the near future accelerate drug development and reduce the hazard of unnecessary drug toxicity without therapeutic benefit.

Sequentiell alternierende Chemotherapie nicht-seminomatöser Hodentumoren mit Velbe/Bleomycin und Adriamycin/Cisplatin

Summary74 patients with disseminated non-seminomatous testicular cancer were randomly entered on a prospective sequential combination chemotherapy regimen with mandatory crossover, consisting of either vinblastine/bleomycin or adriamycin/cis-dichlorodiammineplatinum (II) (DDP) as initial therapy. Independent of the randomization the overall remission rate in 71 evaluable patients was 89% including 54% complete remissions. 35% of the patients remained disease-free at 2+ to 28+ months with a median of 12 months. By additional surgical removal of residual pulmonary metastases in two patients the complete remission rate was increased to 40/71 (56%), and the number of patients with no evidence of disease to 27/71 (38%). According to the life-table method the two-years survival rates were 63% for complete responders and 29% for all other patients, which was significantly lower. 53 patients (75%) were alive at 3 to 28 months with a median of 9 months. Additional advanced abdominal disease, initially elevated β-HCG and LDH and extension of pulmonary disease were of significant negative influence on the prognosis. The evaluation of single chemotherapy courses revealed equal efficacy of both combinations. However, response to adriamycin/DDP occurred in 46% of the courses, when vinblastine/bleomycin had failed, while response to vinblastine/bleomycin occurred only in 21% of the courses when adriamycin/DDP had failed. Thus different patterns of cross-resistance between these alternative regimens may exist.ZusammenfassungVierundsiebzig Patienten mit pulmonal metastasierten nicht-seminomatösen Hodentumoren wurden im Rahmen einer prospektiven randomisierten Phase III-Studie sequentiell alternierend mit Velbe/Bleomycin und Adriamycin/Cisplatin behandelt. Unabhängig von der Randomisierung der initialen Zytostatika-Kombination wurden bei 71 auswertbaren Patienten bei einer Ansprechrate von 89% in 54% der Fälle Vollremissionen erzielt, die bei 35% der Patienten zwischen 2+ und 28+ Monaten mit einem Median von 12 Monaten andauerten. Durch zusätzliche operative Entfernung residueller pulmonaler Solitärmetastasen wurde die Vollremissionsrate auf 40/71 (56%) und die Anzahl der andauernden Vollremissionen auf 27/71 (38%) erhöht. Die Zwei-Jahres-Überlebensrate betrug nach der „Life-table“-Methode 63% bei den Patienten, bei denen eine Vollremission erreicht wurde, und war mit 29% bei den übrigen Patienten statistisch signifikant niedriger. Dreiundfünfzig Patienten (75%) waren bei einer mittleren Überlebenszeit von 9 Monaten zwischen 3 und 28 Monaten am Leben. Zusätzliche fortgeschrittene abdominelle Metastasierung, initial erhöhte β-HCG-und LDH-Werte und das Ausmaß der pulmonalen Metastasierung beeinflußten die Prognose statistisch signifikant negativ. Die Auswertung der einzelnen Chemotherapie-Kurse zeigte, daß beide Zytostatika-Kombinationen gleich wirksam waren. Dabei war jedoch ein Ansprechen auf Adriamycin/Cisplatin in 46% der Fälle nachweisbar, in denen Velbe/Bleomycin versagt hatte, während Velbe/Bleomycin nur bei 21% der Fälle wirksam war, in denen Adriamycin/Cisplatin zu keinem Ansprechen geführt hatte. Eine unterschiedlich ausgeprägte Kreuzresistenz zwischen den beiden Zytostatika-Kombinationen muß daher angenommen werden.: 74 patients with disseminated non-seminomatous testicular cancer were randomly entered on a prospective sequential combination chemotherapy regimen with mandatory crossover, consisting of either vinblastine/bleomycin or adriamycin/cis-dichlorodiammineplatinum (II) (DDP) as initial therapy. Independent of the randomization the overall remission rate in 71 evaluable patients was 89% including 54% complete remissions. 35% of the patients remained disease-free at 2+ to 28+ months with a median of 12 months. By additional surgical removal of residual pulmonary metastases in two patients the complete remission rate was increased to 40/71 (56%), and the number of patients with no evidence of disease to 27/71 (38%). According to the life-table method the two-years survival rates were 63% for complete responders and 29% for all other patients, which was significantly lower. 53 patients (75%) were alive at 3 to 28 months with a median of 9 months. Additional advanced abdominal disease, initially elevated beta-HCG and LDH and extension of pulmonary disease were of significant negative influence on the prognosis. The evaluation of single chemotherapy courses revealed equal efficacy of both combinations. However, response to adriamycin/DDP occurred in 46% of the courses, when vinblastine/bleomycin had failed, while response to vinblastine/bleomycin occurred only in 21% of the courses when adriamycin/DDP had failed. Thus different patterns of cross-resistance between these alternative regimens may exist.

Zur Wirksamkeit von IFN-γ und IFN-α bei der Haarzellenleukämie

SummarySix patients with hairy-cell leukemia were treated with gamma-(IFN-γ) and alpha-(IFN-α-2b) interferon; 3–35 months following splenectomy, treatment was started with 4 × 106 U/m2 IFN-γ sc (iv) every second day for 9–35 weeks. Although the white blood cell counts decreased during therapy from 4.1–49 × 109/1 to 1.5–43 × 109/1, no hematological or clinical improvement was obtained. Subsequently (interval 0–13 weeks), IFN-α-2b was given at an initial dose of 4 × 106 U/m2 sc every second day to all patients. After a treatment period corresponding to that of IFN-γ administration, a significant hematological improvement was observed in five patients (one early death due to pulmonary embolism). At the last follow-up (9–14 months after start of treatment; maintenance therapy, 1 × 106 U every second day), these patients exhibited normal peripheral blood cell counts, and in bone marrow biopsy specimens a marked decrease of hairy cells was seen (1 CR, 3 PR, 1 MR). Adverse reactions including fever, headache, nausea, dryness of the mouth, myalgia, and fatigue did not significantly differ between the two interferon preparations. Whereas IFN-γ is unlikely to have any significant impact on the course of hairy cell leukemia, IFN-α-2b does result in improvement of hematological values and well-being in almost all patients.Zusammenfassung6 Patienten mit einer Haarzellenleukämie wurden 3–35 Monate nach Splenektomie mit IFN-γ (4 × 106 E/m2/2. Tag sc) behandelt. Während einer Therapiedauer von 9–35 Wochen konnte bei keinem Patienten eine signifikante klinische oder hämatologische Befundbesserung erzielt werden. Nach einem therapiefreien Intervall von 0–13 Wochen erhielten alle Patienten IFN-α-2b (zunächst 4 × 106 E/m2/2. Tag, Erhaltungstherapie 1 × 106 E/2. Tag). Zum Zeitpunkt der Beendigung der jeweiligen IFN-α-2b-Gabe war bei 5 von 6 Patienten (1 Patient mit postthrombotischem Syndrom verstarb an einer Lungenembolie) eine deutliche Befundbesserung eingetreten. Nach einer Beobachtungszeit von jetzt 9–14 Monaten konnten 1 CR, 3 PR und 1 MR induziert werden. Die Nebenwirkungen beider Interferon-Präparationen unterschieden sich nicht signifikant.Six patients with hairy-cell leukemia were treated with gamma-(IFN-gamma) and alpha-(IFN-alpha-2b) interferon; 3-35 months following splenectomy, treatment was started with 4 X 10(6) U/m2 IFN-gamma sc (iv) every second day for 9-35 weeks. Although the white blood cell counts decreased during therapy from 4.1-49 X 10(9)/l to 1.5-43 X 10(9)/l, no hematological or clinical improvement was obtained. Subsequently (interval 0-13 weeks), IFN-alpha-2b was given at an initial dose of 4 X 10(6) U/m2 sc every second day to all patients. After a treatment period corresponding to that of IFN-gamma administration, a significant hematological improvement was observed in five patients (one early death due to pulmonary embolism). At the last follow-up (9-14 months after start of treatment; maintenance therapy, 1 X 10(6) U every second day), these patients exhibited normal peripheral blood cell counts, and in bone marrow biopsy specimens a marked decrease of hairy cells was seen (1 CR, 3 PR, 1 MR). Adverse reactions including fever, headache, nausea, dryness of the mouth, myalgia, and fatigue did not significantly differ between the two interferon preparations. Whereas IFN-gamma is unlikely to have any significant impact on the course of hairy cell leukemia, IFN-alpha-2b does result in improvement of hematological values and well-being in almost all patients.